Harinder Singh, Ph.D.
Campus: The Assembly, 5051 Centre Ave
Pittsburgh, PA 15213
- Professor, Department of Immunology
- Director, Center for Systems Immunology
My interests are focused on the analysis of transcription factors and gene regulatory networks (GRNs) that orchestrate the development and functioning of innate as well as adaptive cells of the immune system. As an HHMI Investigator at the University of Chicago, my lab discovered that the Ets family member PU.1 was required for the development of multiple innate and adaptive immune cell lineages. We have systematically illuminated the molecular functions of PU.1 in the development of B cells and macrophages. In a collaboration, we cloned IRF4, a PU.1 partner. IRF4 regulates plasma cell differentiation and its molecular actions are antagonized by the related protein IRF8 to promote the germinal center B cell fate. IRF4 and IRF8 are immune-system specific members of the IRF family of transcriptions factors that have crucial and diverse functions in regulating B and T lymphocytes as well as macrophages and dendritic cells. We have elucidated key activities of IRF4 in the genomic programming of Th17 cells as well as dendritic cells. A notable structural finding has been the discovery of distinct types of composite regulatory elements in immune response genes that are cooperatively bound by IRF4 or IRF8 with the Ets family member PU.1 or the AP-1 member BATF. Using structural and functional genomics as well as computational modeling, we are analyzing coherent networks of transcription factors and the large sets of genomic regulatory sequences through which they act. This is enabling us to assemble GRNs underlying B and macrophage cell fate specification, pre-B and plasma cell differentiation, and the programming of dendritic as well as CD4 T cell responses. We are interested in utilizing the knowledge of GRNs to engineer immune cells with new effector or regulatory capabilities that can be therapeutically harnessed.
- Scott, E.W., Simon, M.C., Anastasi, J. and Singh, H. (1994) Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265:1573-1577.
- DeKoter, R.P. and Singh, H. (2000) Regulation of B lymphocyte and macrophage development by graded expression of PU.1. Science 288:1439-1441.
- Laslo, P., Spooner, C.J., Warmflash, A., Lancki, D., Lee, H-J., Sciammas, R., Gantner, B., Dinner, A. and Singh, H. (2006) Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates. Cell 126:755-766.
- Glasmacher E., Agrawal S., Chang A., Murphy, T.L., Zeng W., Vander Lugt B., Khan, A.A., Spooner C., Rutz S., Hackney J., Escalante C., Ouyang W., Littman, D., Murphy K.M. and Singh H. (2012) A genomic regulatory element that directs assembly and function of immune-specific AP-1/IRF complexes. Science 338:975-980
- Olsson, A., Venkatasubramanian, M., Chaudhri, V., Aronow, B.J., Salomonis, N., Singh, H., Grimes, H.L. (2016) Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature 537:698-702